Post by SLCImmuno at the swaamp:
slcimmuno Member Level Monday, 09/18/17 03:02:48 PM
Re: KMBJN post# 197426
Post # of 197447
Dr. Scott and an HDP-M (C4)… IPIX Anti-Fungal (Candida) – new Published research
A good reminder of more of the IPIX Science / IP; IPIX’s anti-bacterials/anti-fungals, the library of HDP-M compounds the company owns. Maybe someday – via P or B OM / IBD, K (partnership, $$$) – the HDP-M ABX franchise can be revisited
Re Brilacidin – how to partner, I believe Mgmt has signaled it’d keep an open mind as to structuring the deals.
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“Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism” Sci Rep. 2017; 7: 4353. Published online 2017 Jun 28. doi: 10.1038/s41598-017-04462-6
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489528/
Dr. Scott owns stock in Cellceutix, Inc., which owns the patent on compound C4. All other authors declare no financial interests.
http://www.fc-cdci.com/leadership.html
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Abstract
Lethal systemic fungal infections of Candida species are increasingly common, especially in immune compromised patients. By in vitro screening of small molecule mimics of naturally occurring host defense peptides (HDP), we have identified several active antifungal molecules, which also exhibited potent activity in two mouse models of oral candidiasis. Here we show that one such compound, C4, exhibits a mechanism of action that is similar to the parent HDP upon which it was designed. Specifically, its initial interaction with the anionic microbial membrane is electrostatic, as its fungicidal activity is inhibited by cations. We observed rapid membrane permeabilization to propidium iodide and ATP efflux in response to C4. Unlike the antifungal peptide histatin 5, it did not require energy-dependent transport across the membrane. Rapid membrane disruption was observed by both fluorescence and electron microscopy. The compound was highly active in vitro against numerous fluconazole-resistant clinical isolates of C. albicans and non-albicans species, and it exhibited potent, dose-dependent activity in a mouse model of invasive candidiasis, reducing kidney burden by three logs after 24?hours, and preventing mortality for up to 17 days. Together the results support the development of this class of antifungal drug to treat invasive candidiasis.
[...]
Infection by Candida species is the fourth most common nosocomial infection in the blood in the US1. Invasive candidiasis (IC) infections are life-threatening, and while numerous antifungals are used in treatment, including Amphotericin B, azoles and echinocandins, mortality still remains high. Mortality due to IC has been estimated to range from 15–40% for adults2, 3 and 19–31% for neonates and children4, 5.
[…]
Despite their promising attributes, significant pharmaceutical issues, including poor tissue distribution, systemic toxicity, and difficulty and expense of manufacturing, have severely hampered clinical progress. Therefore, a series of non-peptidic analogues of the HDPs (HDP mimics) has recently been developed that have distinct advantages over peptides for pharmaceutical uses22. We have demonstrated that these mimics exhibit potent activity against both bacteria and fungi in vitro and in vivo 23–25. Several studies have demonstrated membrane activity for the HDP mimics against bacteria26, 27. However, the antifungal mechanism of these small molecules is still unknown. As with bacteria, we have observed a lack of resistance development by C. albicans to one such mimic24, suggesting that it may act on the membrane. In our initial studies, two compounds, mPE and PMX519, were identified as anti-Candida compounds from a very limited screen of an HDP-mimic compound library23. A subsequent screen of the library led to the identification of several new compounds with potent anti-fungal activity in vitro against both yeast and hyphal forms, low cytotoxicity to human cells, and strong in vivo activity in two different mouse models of oral candidiasis25. Here we extend these studies to elucidate the mechanism of action and to quantify the activity of one of these lead compounds, compound 4 (C4; see ref. 25 for structure). This compound kills both the yeast form and the hyphal form of C. albicans at the MIC within 5?minutes and 30?minutes, respectively25. We also demonstrate its in vivo activity in a mouse model of invasive candidiasis.
---
The global antifungal drugs market size was valued at USD 10.7 billion in 2015 and is expected to witness growth due to the rising incidence of fungal infections including as pergillosis and candidiasis. These infections may lead to death in patients with a compromised immune system, such as in individuals afflicted with acquired immune deficiency syndrome and leukemia, and are hence termed as opportunistic infections. The increasing prevalence of infectious diseases and hospital-acquired infections is expected to fuel the demand for therapeutics over the forecast period.
Fungal infection is found to attack both superficial and systemic parts of the body, in the skin, eye, mouth, and vagina,leading to diseases, such as athlete's foot, fungal meningitis, and ringworm, which are treated using antifungal products. A wide range of fungicidal preparations,such as creams, sprays, tablets, and injections, are available and increasing adoption of these products is predicted to drive the demand over the next seven years.
slcimmuno Member Level Monday, 09/18/17 03:02:48 PM
Re: KMBJN post# 197426
Post # of 197447
Dr. Scott and an HDP-M (C4)… IPIX Anti-Fungal (Candida) – new Published research
A good reminder of more of the IPIX Science / IP; IPIX’s anti-bacterials/anti-fungals, the library of HDP-M compounds the company owns. Maybe someday – via P or B OM / IBD, K (partnership, $$$) – the HDP-M ABX franchise can be revisited
Re Brilacidin – how to partner, I believe Mgmt has signaled it’d keep an open mind as to structuring the deals.
---
“Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism” Sci Rep. 2017; 7: 4353. Published online 2017 Jun 28. doi: 10.1038/s41598-017-04462-6
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489528/
Dr. Scott owns stock in Cellceutix, Inc., which owns the patent on compound C4. All other authors declare no financial interests.
http://www.fc-cdci.com/leadership.html
---
Abstract
Lethal systemic fungal infections of Candida species are increasingly common, especially in immune compromised patients. By in vitro screening of small molecule mimics of naturally occurring host defense peptides (HDP), we have identified several active antifungal molecules, which also exhibited potent activity in two mouse models of oral candidiasis. Here we show that one such compound, C4, exhibits a mechanism of action that is similar to the parent HDP upon which it was designed. Specifically, its initial interaction with the anionic microbial membrane is electrostatic, as its fungicidal activity is inhibited by cations. We observed rapid membrane permeabilization to propidium iodide and ATP efflux in response to C4. Unlike the antifungal peptide histatin 5, it did not require energy-dependent transport across the membrane. Rapid membrane disruption was observed by both fluorescence and electron microscopy. The compound was highly active in vitro against numerous fluconazole-resistant clinical isolates of C. albicans and non-albicans species, and it exhibited potent, dose-dependent activity in a mouse model of invasive candidiasis, reducing kidney burden by three logs after 24?hours, and preventing mortality for up to 17 days. Together the results support the development of this class of antifungal drug to treat invasive candidiasis.
[...]
Infection by Candida species is the fourth most common nosocomial infection in the blood in the US1. Invasive candidiasis (IC) infections are life-threatening, and while numerous antifungals are used in treatment, including Amphotericin B, azoles and echinocandins, mortality still remains high. Mortality due to IC has been estimated to range from 15–40% for adults2, 3 and 19–31% for neonates and children4, 5.
[…]
Despite their promising attributes, significant pharmaceutical issues, including poor tissue distribution, systemic toxicity, and difficulty and expense of manufacturing, have severely hampered clinical progress. Therefore, a series of non-peptidic analogues of the HDPs (HDP mimics) has recently been developed that have distinct advantages over peptides for pharmaceutical uses22. We have demonstrated that these mimics exhibit potent activity against both bacteria and fungi in vitro and in vivo 23–25. Several studies have demonstrated membrane activity for the HDP mimics against bacteria26, 27. However, the antifungal mechanism of these small molecules is still unknown. As with bacteria, we have observed a lack of resistance development by C. albicans to one such mimic24, suggesting that it may act on the membrane. In our initial studies, two compounds, mPE and PMX519, were identified as anti-Candida compounds from a very limited screen of an HDP-mimic compound library23. A subsequent screen of the library led to the identification of several new compounds with potent anti-fungal activity in vitro against both yeast and hyphal forms, low cytotoxicity to human cells, and strong in vivo activity in two different mouse models of oral candidiasis25. Here we extend these studies to elucidate the mechanism of action and to quantify the activity of one of these lead compounds, compound 4 (C4; see ref. 25 for structure). This compound kills both the yeast form and the hyphal form of C. albicans at the MIC within 5?minutes and 30?minutes, respectively25. We also demonstrate its in vivo activity in a mouse model of invasive candidiasis.
---
The global antifungal drugs market size was valued at USD 10.7 billion in 2015 and is expected to witness growth due to the rising incidence of fungal infections including as pergillosis and candidiasis. These infections may lead to death in patients with a compromised immune system, such as in individuals afflicted with acquired immune deficiency syndrome and leukemia, and are hence termed as opportunistic infections. The increasing prevalence of infectious diseases and hospital-acquired infections is expected to fuel the demand for therapeutics over the forecast period.
Fungal infection is found to attack both superficial and systemic parts of the body, in the skin, eye, mouth, and vagina,leading to diseases, such as athlete's foot, fungal meningitis, and ringworm, which are treated using antifungal products. A wide range of fungicidal preparations,such as creams, sprays, tablets, and injections, are available and increasing adoption of these products is predicted to drive the demand over the next seven years.
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